N{HU 1{B -oxides of adenosine-5{40 -carboxylates for treating angina

ABSTRACT

WHEREIN R1 is loweralkyl, lowerhydroxyalkyl or lowerhaloalkyl, and R2 and R3 each are hydrogen or acyl or when taken together form an isopropylidene or a benzylidene moiety, and the pharmaceutically acceptable acid addition salts thereof. The compounds are useful as anti-anginal agents.   N1-Oxides of adenosine-5&#39;&#39;-alkyl carboxylates represented by the structural formula

United States Patent 1191 Prasad [4 5] Dec. 23, 1975 N-OXIDES OF ADENOSINE-S '-CARBOXYLATES FOR TREATING ANGINA [75] Inventor: Raj Nandan Prasad, Pierrefonds,

Canada [73] Assignee: Abbott Laboratories, North Chicago, Ill.

22 Filed: May 21, 1974 211 Appl. No.: 472,030

Related US. Application Data [62] Division of Ser. No. 294,741, Oct. 3, 1972,"Pat. N0.

Primary Examiner-Jerome D. Goldberg Attorney, Agent, or Firm-Robert L. Niblack; Vincent A. Mallare [57] ABSTRACT N -oxides of adenosine-5'Falkyl carboxylates represented by the structural formula wherein R is loweralkyl, lowerhydroxyalkyl or lowerhaloalkyl, and R and R each are hydrogen or acyl or when taken together form an isopropylidene or a benzylidene moiety, and the pharmaceutically acceptable acid addition salts thereof. The compounds are useful as anti-angina! agents. 1

3 Claims, No l ii'awings N -OXIDES OF ADENOSINE--CARBOXYLATES FOR TREATING ANGINA This is a division of application Ser. No. 284,741 filed Oct. 3, 1972, now US. Pat. No. 3,830,793, issued Aug. 20, 1974.

BACKGROUND OF THE INVENTION excitement or any other stressful situation. In summation, any sudden increase in cardiac work, any decrease in coronary blood flow or any interference with oxygenation of the blood may cause an attack. However, anginal attacks can occur while the patient is sleeping. Therefore, angina] pain is not necessarily due to a decrease of blood flow but rather to an insufficiency of the flow in relation to the metabolic requirements or oxygen demands of the heart.

There are several available drugs useful in the management of angina pectoris attacks. Most of the therapeutic agents, such as nitroglycerin and related nitrates are coronary dilators which do not effect the underlying coronary artery pathology or myocardial cardiac damage. Accordingly, currently available therapy is symptomatic rather than curative. Nitroglycerin is probably the most widely used agent in managing acute attacks of angina; however, there has been a long standing need for a prophylactic agent which, when administered to patients with a history of, or who are susceptible to attacks of angina pectoris, will prevent or reduce the severity of future attacks.

The present invention provides a novel class of compounds which are orally active, long-acting anti-angina] agents.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N -oxides of adenosine-5-alkyl carboxylates, to therapeutic compositions containing such compounds asthe active ingredient, to methods of making and using the compounds and to intermediates useful in the preparation of the compounds. V

The compounds of this invention are represented by the structural formula 2 N1 i613 o u R10- 0 wherein R is loweralkyl, lowerhydroxyalkyl or lowerhaloalkyl, and R and R each are hydrogen or acyl or when taken together form an isopropylidene or a benzylidene moiety, and the pharmaceutically acceptable acid addition salts thereof. The compounds are useful as anti-anginal agents.

The term loweralkyl, as used herein, refers to both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms including methyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,.isopentyl, neo-pentyl, n-hexyl, and the like.

The term halo refers to chloro, bromo, fluoro or iodo.

The terms lowerhydroxyalkyl and lowerhaloalkyl refer to the above defined C C alkyl groups substituted with a hydroxy or a halo radical.

The term pharmaceutically acceptable acid addition salts refers to salts prepared by reacting the ester with an organic or inorganic acid. Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate, napsylate and the like.

The term acyl refers to acetyl, propionyl, butyryl, and the like.

Compounds of this invention wherein R and R are hydrogen are useful as anti-anginal agents at dosages of 0.025 to 30 mg./kg. of body weight daily. The compounds can be administered to angina pectoris patients by either oral or parenteral routes, however the oral route of administration is preferred. While the compounds can be administered in a single dose, it is preferred to administer them in divided dosages, i.e., three to four times daily.

The anti-angina] activity of the compounds of this invention was first established using the method of Schoepke et al., Pharmacologist 8: 204 (1966).

Compounds of this invention wherein R and R are acyl or when taken together form an isopropylidene or benzylidene moiety are useful as intermediates for pre-- paring compounds wherein R and R are hydrogen.

The compounds of this invention can be prepared by forming the N -oxide of 2',3' is0propylidene adenosine carboxylic acid, cleaving the 2,3-isopropylidene group to obtain the N -oxide of adenosine-5-carboxylic acid, and reacting the acid with. the appropriate alcohol (R OH) in the presence of, for example, thionyl chloride to obtain the desired product. The reaction is represented by the following reaction sequence.

0 lAcOH IICOOII The following examples further illustrate this invention.

EXAMPLE 1 ADENOSINE-S '-CARBOXYL1C ACID-N OXIDE A suspension of 2,3-0-isopropylidene adenosine-S carboxylic acid [Harmon et al., Chem. & lnd., ll4( 1969)] (9.6 g, 0.03 mole) in acetic acid (750 ml.) and H 100 ml. of 30% aqueous solution) was stirred at the room temperature. After 7 days, the reaction mixture was filtered to remove a small amount of suspended material (0.2 g.). The filtrate was cooled to l0l5C and the excess of H 0 was destroyed by adding 5% Pd/C (6 g.). The dark mixture was filtered, concentrated under reduced pressure to 75 ml. and poured on to stirred ether (200 ml. The gray solid was recrystallized from water to give 3.6 g. (dried at 120C/6 hrs.) of adenosine-5'-carboxylic acid-N- oxide, m.p. 220 (dec.) contaminated with traces of 2',3-0-isopropylidene adenosine-5'-carboxylic acid- N -oxide. This material was found to be suitable for the synthesis of its derivatives. 1

To obtain the pure acid, a small amount (0.84 g.) of the above acid was taken up in 35 ml. of 50% formic acid. After 3 days at room temperature, the clear solution was evaporated under reduced pressure to dryness. The residue was triturated several times with methanol and filtered, and the residue (0.5 g.) was recrystallized from water to give analytically pure adenosine-5-carboxylic acid-N -oxide, m.p. 220 (dec). The structure was confirmed by NMR.

Anal. Calcd. for C H N O C, 40.40; H, 3.71; N,

23.56; 0, 32.32. Found: C, 40.44; H, 3.76; N, 23.84; 0, 32.68.

EXAMPLE 2 ADENOSlNE-S ETHYL)CARBOXYLATE-N OXIDE Thionyl chloride (2 ml.) was added dropwise to a suspension of adenosine-5'-carboxylic acid-N -oxide (1.8 g., 0.006 mole) in absolute ethanol (100 ml.) at 5-l0C. After 30 minutes at 5l0C, the clear solution was stirred for 16 hours at the room temperature. At the end of this period, the mixture was kept at 50C for one-half hour, concentrated under reduced pressure to approximately 20 ml. and poured onto stirred ether (150 ml.). The precipitate was filtered and the residue was stirred with aqueous NaHCO (20 m1.) at

sired product, m.p. l97-200C. Recrystallization from absolute ethanol gave the analytical sample as a semihydrate, m.p. 204206C, [a],,, 22 20 (C 0.65 in IN HCl). Infrared and NMR spectra confirmed the structure.

Anal. Calcd. for C H, N O /2 H O C, 43.11; H,

4.78; N, 20.95. Found: C, 42.84; H, 4.64; N, 20.72.

EXAMPLES 3-1 1 The following compounds are prepared following the procedure of Example 2 by replacing ethanol with the appropriate alcohol.

Adenosine-S n-butyl )carboxylate-N oxide, using n-butanol.

Adenosine-S '-(methyl )carboxylate-N -oxide using methanol.

Adenosine-S -(iodoethyl )carboxyla'te-N oxide using iodomethyl alcohol.

Adenosine-S n-pentyl )carboxylate-N oxide using pentanol.

Adenosine-S n-hexyl )carboxylate-N oxide hexanol.

using The compounds of this invention can be formulated into various pharmaceutical dosage forms such as tablets, capsules, pills and the like, for immediate or sustained release, by combining the active compound with suitable pharmaceutically acceptable carriers or diluents according to methods well known in the art. Such dosage forms may additionally include excipients, bind- 1 ers, fillers, flavoring and sweetening agents and other therapeutically inert ingredients necessary in the formulation of the desired pharmaceutical preparation.

I claim:

1. A method of increasing coronary sinus partial pressure of oxygen in an angina pectoris patient in need of such treatment comprising administering to said patient a dosage of from 0.025 to 30 mg/kg. of body l0l5C and filtered to give 0.8 g. (45%) of the deweight daily of a compound of the formula body weight daily of a pharmaceutical composition comprising a compound of the fonnula wherein R is loweralkyl, lowerhydroxyalkyl or lower haloalkyl, and R and R each are hydrogen, acetyl, propionyl, or butyryl, or when taken together form an isopropylidene or benzylidene moiety; or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent. 

1. A METHOD OF INCREASING CORONARY SINUS PARTIAL PRESSURE OF OXYGEN IN AN ANGINA PECTORIS PATIENT IN NEED OF SUCH TREATMENT COMPRISISNG ADMINISTERING TO SAID PATIENT A DOSAGE OF FROM 0.025 TO 30MG./KG. OF BODY WEIGHT DAILY OF A COMPOUND OF THE FORMULA
 2. The method of claim 1 wherein said compound is adenosine-5''-(ethyl)carboxylate-N1-oxide or a pharmaceutically acceptable acid addition salt thereof.
 3. The method of claim 1 where there is administered to said patient a dosage of from 0.025 to 30 mg./kg. of body weight daily of a pharmaceutical composition comprising a compound of the formula 